Colorectal cancer is among the leading causes of cancer-related morbidity and mortality in industrialized nations. Patients diagnosed at an early stage, prior to lymph-node spread, are potentially cured with surgery. While many patients are diagnosed at an early stage, most patients frequently undergo peri-operative radiation and/or chemotherapy to attempt to control the metastatic spread of disease. Ultimately, many patients thought to have undergone curative resections eventually develop recurrent disease. Factors that enhance survival include accurate and early diagnosis and prediction of survival and response to therapy, as colon and rectal cancers are often silent and slowly progressive.
Thus, there is a need for identifying colon cancer early in the course of the disease process, and a particular need for identifying cancers that are chemoresistant. More specifically, since it is understood in the art that the behavior of cancer cells, both regarding their tumorigenicity and their resistance to chemotherapeutic drugs is mediated by the expression of a not completely defined set of particular genes, there is a need to identify genes and collections or sets of genes that serve as effective molecular markers for chemoresistance in colon cancer, as well as such genes or gene sets that provide clinically effective therapeutic targets for colon cancer.
The majority of oncologic therapeutics specifically target proteins in cancer cells, therefore measurement of protein expression is important in determining the potential efficacy of such therapeutics. Assays detecting thymidylate synthase (TS) in tissue samples are known and studies investigating the relationship between TS expression and survival in colorectal cancer patients have been done. Most have shown poorer overall survival and progression free survival with high TS expression but results have varied widely and the precise prognostic value of TS is not yet known (Popat et al Journal of Clinical Oncology 22(3) Feb. 1, 2004, Thymidylate Synthase Expression and Prognosis in Colorectal Cancer: A Systematic Review and Meta-Analysis. New methods for consistent measurement of TS is tissue sections are needed.
Thymidylate synthase (TS) catalyzes the reductive methylation of deoxyuridylate for production of dTTP, which is critical for DNA synthesis. The regulation of its expression has been shown to be critical in modulation of response to 5-FU, a longstanding chemotherapeutic agent for colon cancer. High expression levels have been shown to be a marker for decreased survival and response to therapy. Recently, it has been demonstrated that TS may have other cellular functions, including post-transcriptional regulation.